Derivatives of dibenzo[a, e]cycloheptatriene



a United States Patent Ghice This invention relates to derivatives ofdibenzo'[a,e]- cycloheptatriene and particularly to those having thestructure:

Compound I..- alkyH-(S hydroxy 5 dibeuzo[a,e]cyclhcptatrienyl)-pipcrdine (when there is a double bond between 10 and 11 Cs) (when R isalkyl) and Compound II.1 alkyl 4 (5 dibenzoiae] eycloheptatrienylidene)piperidine (when there is a double bond between and 11 Gs) (when R isalkyl) in which R is-hydrogen or lower alkyl or alkenyl containing up to4 carbon atoms and which may be straight or branched chained.

The alkyl radical may be substituted, for example, with a hydroxy, amesyloxy or an amino group. The presence of either a single bond or adouble bond between the 10 and 11 carbon atoms is indicated by thedotted line. The numbering of the dibenzocycloheptatriene ring systemconforms to the Ring Index, number 2077.

The radicals X and X may be hydrogen or a halogen which particularly ischlorine, bromine or fluorine, but X and X may as well be radicals suchas trifluoromethyl, lower alkyl having up to four carbon atoms, loweralkoxy having up to four carbon atoms, or a mononuclear aryl radicalsuch as phenyl. The radicals X and X may be similar or may be dissimilarand each benzene ring may have one or two of the aforementioned radicalsattached to it.

One or more of the hydrogens in positions 2, 3, 5, and 6 of thepiperidine ring may be replaced by alkyl groups so long as the totalnumber of carbon atoms in all such substituent alkyl groups does notexceed four. The invention also contemplates the N-oxides of compound I,which may be prepared from the bases by known methods.

The compounds represented by the structure I are useful as intermediatesand may be sold commercially for making the compounds of structure II.The compounds of structure II possess antiserotonin and antihistamineactivity. They may be administered to persons in any of the usualpharmaceutical oral forms such as powders, capsules, tablets, elixirsand aqueous suspensions, in the amount of from l to 250 milligrams perdose taken 2 to 4 times a day. For sterile solutions, for injection,from 0.1 to 50 milligrams would be injected per dose 2 to 4 times a day.The compound II may most easily be administered as a salt and anyconvenient, nontoxic acidsuch as hydrochloric acid may be used for thispurpose and these salts are considered to be equivalent to the bases.

To prepare the compounds of the invention, theknown compounddibenzo[a,e]cycloheptatrien-S-one and its 10,11-dihydro derivative areused as starting materials and they are hereinafter referred togenerically as dibenzo[a,e]cycloheptatrien-S-ones. They may be preparedby using the process described by -A. C. Cope et al., entitled CyclicPolyolefins, [XV. 1-methylene- 2,3,6,7-dibenzo-cycloheptatriene,appearing in I. Am.

Chem. Soc. 73, 1673-1678 (1951)]. Or the starting compounds andparticularly those having sub'stituents on the benzene rings may be madeby following the teachings of T. W. Campbell et al., in an articleentitled Synthesis of 2'-acetamido-2,326-,7-dibenzotropilidene andZ-acetamido-19,9-dimethylfluorene, appearing in Helv. Chim. Acta 36,1489-1499 (1953). The preparation of specific starting materials isreferred to in the subsequent examples.

The selected dibenzo[a,e]cycloheptatrien-S one (III) is condensed with a1-alkyl-4-piperidylmagnesium halide (IV) employing tetrahydrofuran asthe solvent, the precautions usually taken to exclude air and moisturefrom the apparatus during Grignard reactions being observed. (See Step Bhereinafter.) This 1-alkyl-4- piperidylmagnesium halide may be eitherthe bromide or the chloride but is preferably the chloride.

The Grignard reagent may be prepared as follows: The selected1-alkyl-4-piperidone is reduced to the carbinol by the method describedby S. M. McElvain and K. Rorig, J. Am. Chem. Soc. 70, 1826 (1948). Thel-alkyl-4-piperidinol then may be converted to the l-alkyl-4-chloropiperidine as described by these authors or to the1-alkyl-4-bromopiperidine by the method employed by A. Einhorn, Ber. derDeutschen Chemischen Gesellschaft 23, 2891 (1890) for the conversion oftropine to 3-bromotropane. The Grignard reagent is then prepared bycombining the -1-alkyl-4-halopiperidine with magnesium, preferably usingtetrahydrofuran as the solvent. The usual maintenance of dry conditionsshould be observed. This may be represented as follows:

R IV

Step A The Grignard reagent and the dibenzo[a,e]cycloheptratrien-S-oneare combined according to the following equation:

I 1 R Step B The condensation reaction of StepB is preferably initiallycarried out at low temperature for example cooling by means of an icebath and finally may, continue at room temperature. It has been foundthat tetrahydrofuran is an. excellent solvent for carrying out thereaction of Step B and the source of this may be the solution obtainedin Step- A. The dibenzo[a,e]cycloheptatrien-S-one can be added directlyto the reaction mixture in which the Grignard reagent IV was prepared.However, any inert solvent for the reactants of Step B may be employed.

After the reaction of Step'B is completed the bulk of the solvent isremoved by vacuum distillation, the Grignard adduct dissolved in benzeneand hydrolyzed by the addition of water or ammonium chloride soiutionwith cooling. Compound I is recovered from the benzene solution. p

Compound I is dehydrated to produce Compound 11, as is represented bythe following:

CQ .0 H X Step Compound IH2O-) Compound 11 The dehydration of compo-undl may be effected by means of such commonly used dehydrating agents asacetyl chloride or acetic anhydride but alternatively o-sulfobenzoicanhydride may be used. The alcohol may be dehydrated directly or may befirst converted to a salt such as the hydrochloride, hydrob rornide orsulfate. Conversion to a salt prior to dehydration is preferable in somecases. The reactionmay be carried out in an excess of dehydrating agentas so-lvent, or employing a solvent such as chloroformpi: glacial aceticacid. Thesolvent then is removed by vacuum distillation and the compoundII in the form of a salt is crystallized from a suitable 501-.

vent.

The following examples will further illustrate the invention:

4 EXAMPLE 1 1ritethyl-4-(5-dibenzo[a,e]cycloheptatrienyliden)-piperidinehydrochloride and I-mefhyl-4 -(5-dibenzo[a,e]- cycloheptatrieny lidene-piperidine STEP A.PREPARATION OF l-METHYL -IIPERIDYL- MAGNESIUMCHLORIDE Magnesium turnings (5.45 g., 0.22 g. atom) were placed in a 500ml. S-necked flask provided with a condenser, Hershberg stirrer anddropping funnel and protected with a drying tube. An atmosphere of drynitro gen was maintained in the apparatus throughout the reaction. Themagnesium was covered with 20 ml. of dry tetrahydr'ofuran. A crystal ofiodine and 1.2 g. of ethyl bromide were added and after the reaction hadsubsided (formation of ethylmagnesium bromide) a solution of 29.4 g.(0.22 mole) of 4-chloro-1-methyl-piperidine in dry tetra-hydrofuran(total volume, 103 ml.) was added dropwise at such a rate that gentlereflux was maintained. The solution of 4-chloro-l-methyl-piperidine intetrahydrofuran was dried over calcium hydride at icebath temperatureprior to use. When the addition of the halide was complete the reactionmixture was refluxed with stirring for 1 hour. in some subsequentexperiments this period of refluxing was omitted with no deleteriousresult.

STEP B.PREPARATION on l-METHYL- l-(S-HYDROXY- 5DIBENZO[A,E]CYCLOHEPTATRIENYL) PIPERI- DINE The solution of the Grignardreagent prepared in step A was cooled to 5 to 10 C. and stirred while22.7 g. (0.11 mole) of dibenzo[n.e]cycloheptatrien-5one was added inportions. After stirring for 1 hour during which time the reactionmixture was allowed to warm up to room temperature, the bulk of thetetrahydrofuran was distilled at 4050 C. under reduced pressure.Benzene, 150 ml., was added and the reaction mixture stirred and cooledin an iee-bath while water, ml., was added gradually. The benzene layerwas separated by decantation and the gelatinous residue extracted threetimes with 75 ml. portions of boiling benzene. The solvent wasevaporated from the combined benzene extracts to give 33 .4 g. of aclear light brown resin. Crystallization from an alcohol-water mixturegave 19.5 g. of 1-methyl-4-(5- hydroxy 5dibenzo[a,e]cycloheptatrienyl)-piperidine, M.P. 156-157 C. Tworeci'yst-aliizations from alcoholwater mixtures followed by tworecrystallizations from benzene-hexane mixtures gave analytically pureproduct, M.P., 166.7l67.7 C.

Analysis-Calculated for C21HZ'3NOZ C, 82.59; H, 7.59; N, 4.59. Found: C,82.39; H, 7.67; N, 4.58.

STEP C.PREPARATION OF I-METI-lYL Q-(RDIBENZO [A,E]CYCLOHEP'IATRIENYLIDENE -PIPERIDINE HY- DROCHLORIDE 1 methyl 4-(5hydroxy-S-diben'zo[a,e]cycloheptatrienyl)-piperidine (3.05 g., 0.01mole) was dissolved in glacial acetic acid, 15 ml. The solution wassaturated with dry hydrogen chloride with external cooling. A whitesolid separated. Acetic anhydride (3.07 g., 0.03 mole) was added and themixture heated on the steam-bath for 1 hour. The solid dissolved in thefirst 5 minutes of the heating period. The reaction mixture was pouredinto 25 ml.of water and the mixture made strongly basic with 10 N sodiumhydroxide solution. The mixture was extracted three times with 50 ml.portions of benzene, the combined extracts washed with water andconcentrated to a volume of approximately 50 ml. The solution wassaturated with dry hydrogen chloride and the while crystalline productcollected and dried. The yield of product, M.P. 251.6242.6C. (dec.) was2.5 g. Recrystallization from a mixture of absolute alcohol and absoluteether gave a product, M.P. 252.6253.6 C. A sample was analyzed afterdrying for 7 hours at over phosphorus pentoxide in vacuo. i

Analysis.-Calculated for C H N-HCl: C, 77.88; H, 6.85; N, 4.33. Found:C, 77.60; H, 6.80; N, 4.31. STEP D.PREPARATION OF l-METHYL-l-(5-DIBENZO[A,E] CY CLO HEPTATRIENYLIDENE -PIPERIDINE The hydrochloride salt, 4.3g., was suspended in 100 ml. of warm water and the mixture made stronglyalkaline by the addition of 15 ml. of 5% sodium hydroxide. The mixturewas extracted with four 50 ml. portions of henzene and the extractsdried over sodium sulfate. Evaporation of the benzene on the steam-bathat reduced pres sure left 3.7 g. (97%) of the base, M.P., 110.3-lll.3 C.Recrystallization from a mixture of alcohol and water gave product,M.P., 112.3113.3 C.

Analysis-Calculated for C H N: C, 87.76; H, 7.37; N, 4.88. Found: C,87.77; H, 7.47; N, 4.87.

EXAMPLE la 1 methy l-4- 5 -di benzo {a,e*] cycloh eptaltrierzy Z id cne-p iperidine hydrochloride hydrate 1 methyl-4-(5-dibenzo[a,e]cycloheptatrienylidene) -piperidine (0.400 g., 0.00139 mole) as obtainedin Example I, was dissolved in 55 ml. of 1 N hydrochloric acid at theboiling point. The solution was allowed to cool to room temperature andto stand for 24 hours. The crystalline product was collected and driedin a vacuum desiccator over concentrated sulfuric acid and soda lime for6 hours. The product then was pulverized and dried over calcium chlorideand soda lime at 0.1 mm. for approximately 65 hours. The yield of driedproduct was 0.420 g. In a melting point determination, this substancesintered at 190 C. and melted at 214216 C. when heated at a rate of 6per minute from 180 C.

Anaylsis.Calculated for C H N-HCl-H O: C, 73.76; H, 7.08; N, 4.10; C1,10.37. Found: C, 73.69; H, 7.31; N, 4.19; C1, 10.36.

EXAMPLE lb 1 -mefhyl-4-(5-dib enzo [at,e]cyclh epta rrienylidene)piperidine hydrogen m'aleate l methyl 4dibenzo[a,e]cycloheptatrienylidene)- piperidine (0.400 g., 0.00139 mole)as obtained in Example I, was dissolved in 8 ml. of absolute alcohol. Asolution of 0.170 g. (0.00147 mole) of maleic acid in 4 ml. of absolutealcohol was added and the resulting solution diluted to incipientcrystallization with absolute ether. The product melted at 187-188 C. Itwas recrystallized from a mixture of isopropyl alochol and ether with nochange in melting point.

Analysis.Calculated for C H N-C H O C, 74.41; H, 6.25; N, 3.47. Found:C, 74.17; H, 6.31; N, 3.64.

EXAMPLE II 1-is0pr0pyl-4-(5-dibenz0[a,e]cycloheptatrienylidene)piperidine STEP A.PREPARATION 0F 1-ISOPROPYL 4-PIPERIDYLMAGNESIUM CHLORIDE By substituting an equimolecular quantity of4-chlorol-isopropylpiperidine for the 4-chloro-l-meth-yl-piperidine ofExample I, Step A, and following substantially the pro cedure of ExampleI, Step A, a solution of l-isopropyl- 4-piperidylmagnesium chloride intetrahydrofuran is obtained.

STEP B.PREPARATION OF 1ISOPROPYL-4-(5-HY- DROXY 5DIBENZO[A,E]CYCLOHEPTATRIENYL-PI- PERIDINEDibenzo[a,e]cycloheptatrien-5-one is added to the solution of theGrignard reagent obtained in Step A, and

the product isolated as described in Example I, Step B.

STEP C.PREPARATION 0F 1-ISOPROPYL-4-(5-DIBEN- Z0 [A,E]CYCLOHEPTATRIENYLIDENE -PIPERIDINE The1-isopropyl-4-(5-hydroxy-5-dibenzo[a,e] cycloheptatrienyl)-piperidineobtained in Step B is dehydrated as 6 described in Example I, Step C, togive 1-isopropyl-4- (S-dibenzo[a,e]cycloheptatrienylidene)-piperidinethat is isolated in the form of the hydrochloride salt.

EXAMPLE III I -butyl-4- (5 -dibe'nzo [me] cycloh epzatrienylidenepiperidine STEP A'.PREPARATION OF 1-BUTYL-4PIPERIDYL- MAGNESIUM CHLORIDEBy substituting an equimolecular quantity of 4-chloro-1- butylpiperidinefor the 4-chloro-l-methylpiperidine of Example I, Step A and followingsubstantially the procedure of Example I, Step A, a solution ofl-butyl-4- piperidylmagnesium chloride in tetrahydrofuran is obtained.

STEP B.PREPARATION OF 1-BU'1YL-4-(5-HYDROXY-5- DIBENZO [A,E]-CYCLOHEPTA'TRIENYL -P IPERIDINE Dibenzo[a,e]cycloheptatrien-S-one isadded to the solution of the Grignard reagent obtained in Step A and theproduct isolated as described in Example I, Step B.

STEP C.-PREPARATION 0F l-BUTYL4-(5-DIBENZO [A,E CYCLOHEPTATRIENYLIDENE-PIPER IDINE The 1-butyl-4- S-hydroxy-S -dibenzo [a,e]cycloheptatrienyl)-piperidine obtained in Step B is dehydrated asdescribed in Example I, Step C to give 1-butyl-4-(5- dibenzo[a,e]cycloheptatrienylidene)-piperidine that is isolated in the form of thehydrochloride salt.

EXAMPLE IV 1-mezhyl-4-(5-dibenzo[ma] cyclo-heptazrienylidene) piperidineN-o xide A solution of 3.0 g. (0.0104 mole) of 1-methyl-4-(5-dibenzo[a,e]cycloheptatrienylidene)-piperidine in 30 ml. of absolutemethanol was stirred and cooled in an ice-bath while 3.5 g. of 30%hydrogen peroxide was added dropwise over a 5 minute period. A colorlesssolid separated while the mixture was being stirred in the cold. After15 minutes the ice-bath was removed and stirring was continued for 3hours at room temperature. During this period the solid dissolved togive a clear pale yellow solution. After 22 hours the solution wascooled in an icebath and treated with an aqueous suspension of platinumblack. After stirring for 1 hour at room temperature a test for peroxidewas negative and the mixture was filtered through a mat of diatomaceousearth. The solvent then was evaporated under reduced pressure keepingthe temperature below 35 C. The residue, a glass-like resin, waspulverized. It became partially crystalline on further drying. Afteradditional drying over phosphorus pentoxide at 0.1 mm. pressure, theproduct gave elementary analyses agreeing well with the valuescalculated for the hernihydrate.

Analyser-Calculated for c ,n ,No- /2H,o: C, 80.71; H, 7.10; N, 4.48.Found: C, 80.77; H, 7.36; N, 4.58.

A sample from another experiment that was subjected to further dryinggave the following analyses:

Armlysis.-Calculated for C H NO: C, 83.00; H, 6.97; N, 4.61. Found: C,82.58; H, 7.37; N, 4.59.

EXAMPLE V 1-mcthyl-4( I 0,11-dihydr0-5-dibenz0[nae]cycloheptatrienylidene) -piperidine hydrochloride STEP A.-PREPARATION OF1-\'IETHYL-4PIPERIDYL- MAGNESIUM CHLORIDE The Grignard reagent wasprepared from 227 g. (0.0921 g. atom) of magnesium and 12.3 g. (0.0921mole) of 1-methyl-4-piperidyl chloride in approximately ml. oftetrahydrofuran, following the procedure of Example I, Step A.

7 STEP B.PREPARATION OF LMETHYLA-(IOJl-DIHY- DROHYDROXY-zS-DIBENZO[A,E]CYCLOHEPTA- TRIENYL)-PIPERIDINE 10,1l-dihydrodibenzo [a,e] cycloheptatriene-5one (9 .5 8 g., 0.046 mole) wasadded to the Grignard solution of StepA and the product was isolatedsubstantially as described in Example I, Step B. The l-methyl-4-(10,11-dihydro 5 hydroxy 5 dibenzo[a,e] cycloheptatrienyl)- piperidine, M.P.179-l81 C. weighed 8.3 g. (59%) after recrystallization from a mixtureof alcohol and water. A further recrystallization gave product, M.P.180- 181 C.

Analysis.Calculated for C H NO: C, 82.04; H, 8.20; N, 4.56. Found: C,81.79; H, 7.93; N, 4.64. STEP C.PREPARATION OF 1-METHYL-4-(10,11-DIHY-DRO-5-DIBENZO {A,E] CYCLOHEPTATRIENYLIDENE) PIPERIDINE HYDROCHLORIDE 1methyl 4 (10,11 dihydro S hydroxy 5dibenzo[a,e]cycloheptatrienyl)-piperidine (6.3 g., 0.0205 mole) wasdehydrated following substantially the procedure of Example 1, Step C.The hydrochloride of 1- methyl 4 (10,11 dihydro 5dibenzo[a,e]cycloheptatrienylidene)-piperidine was obtained in a yieldof 5.89 g. (99%), M.P. 273-274 C. (with decomposition).Recrystallization from a mixture of isopropyl alcohol and ether did notchange the M.P.

Anaiysis.Calculated for C H N-HCl: C, 77.40; H, 7.42; N, 4.29; Cl,10.88. Found: C, 77.23; H, 7.46; N, 4.4-5; Cl, 10.7 6.

EXAMPLE VT 1 -mathy[-4-(3-chl0r0-5-dibenz0 [a,e]cycloheptatrienylidene)-piperidine hydrogen malcate STEP A.-PREPARATIONOF l-METHYL--PIPERID "L- MAGNESIUM CHLORIDE The Girgnard reagent wasprepared from 2.43 g. (0.1)

g. atom), of magnesium and 13.36 g. (0.1 mole) of1-methyl-4-chloropiperidine in approximately 90 ml. of

tetrahydrofuran, following the procedure of Example 1,

Step A and omitting the final period of heating.

STEP B.-PREPARATION OF 1METHYL-'4-(3-CHLORO- 5 HYDROXY 5 DIBENZO[A,E]CYCLOHEPTATRI- ENYL)-PIPERIDINE The solution of the Grignard reagentprepared in step A was cooled to 510 C. and stirred at this temperaturewhile 3-chlorodibenzo[a,e]oycloheptatrien-S-one (12.03

g., 0.05 mole) was added. The product was isolated essentially asdescribed in Example I, step B. The yield of product, M.P., 94.595.5 C.was 9.6 g. (54%). Recrystallization from a mixture of alcohol and Waterraised the M.P. to 9597 C. After a second recrystallization the M.P. wasincreased to 199-200 C. The yield of this material was 5.4 g. (32% Afurther recrystallization from a mixture of alcohol and Water followedby a recrystallization from benzene and hexane did not change the M.P.

Analysis-Calculated for C H C1NO: C, 74.21; H,

6.53; N, 4.12. Found: C, 73.90; H, 6.39; N, 4.01.

The 3 chlorodibenzo[a,e]cycloheptatrien 5 one employed in step B wasprepared by the following sequence.

3-(p-chlorobenzylidene)-phthalidewas prepared from pchlorophenylaceticacid and phthalic anhydride following essentially the method for thepreparation of benzalpthalide described in Organic Syntheses CollectiveVolume II, page 61 (John Wiley and Sons, 1948). The3-(pchlorobenzylidene)-phthalide was reduced to2-(p-chlorophenethyl)-benzoic acid with phosphorus and hydriodic acid,essentially as described by A. C. Cope and S. W.

Fenton [1. Am. Chem. Soc. 73, 1673 (1951)] for the reduction ofbenzalphthalide. The cyclization of 2-(pchlorophenethyD-benzoic acid to3-chloro-10,11-dihydrodibenzocycloheptatrien-S-one was accomplished byheating with polyphosphoric acid substantially as described by T. W.Campbell, R. Ginsig and H. Schmid, Helv. Chim.

Acta 36 1489 (1953). he3-chloro-10,ll-dihydrodienzocycloheptatrien-S-one was brominated with N-bromosuccinimide and converted to 3-chlorodibenzo[a,e]

cycloheptatrien-S-one essentially as described by Cope and Fenton [1.Am. Chem. Soc. 73, 1673 (1951)].

STEP C.PREPARATION OF 1-METHYL-4-(aCHLORo- 5DIBENZO[A,E]CYCLOHEPTATRIENYLIDENE) PI- PERIDENE HYDROGEN MALEATE1-methyl-4-(3-chloro-5-hydroxy 5dibenzo[a,e]cycloheptatrienyl)-piperidine (0.65 g., 0.00192 mole) andosulfobenzoic anhydride (3.68 g., 0.02 mole) were mixed and heated to135-140 C. for minutes. The solid that formed on cooling was ground upand mixed with water. The m xture was made strongly alkaline andextracted with benzene. After washing with water the benzene wasevaporated on the steam-bath under reduced pressure. The residue, aclear brown gum, was dissolved in benzene and the solution diluted withhexane. A

small quantity of an insoluble solid was separated by filtration and thesolvent evaporated. The clear light yellow residue weighed 0.16 g. Itwas dissolved in 15 ml. of absolute ether and treated with a solution of0.064 g. of maleic acid in 3 ml. of absolute alcohol. The

white crystalline product, M.P., 197l98 C. Weighed 0.08 g.Recrystallization from a mixture of alcohol and ether did not change theM.P.

Analysis.Calculated for C H ClN-C H O C, 68.57; H, 5.52; N, 3.20; Cl,8.10. Found: C, 68.39; H, 5.47; N, 3.27; Cl, 7.91.

EXAMPLE VII 4-(5-dibenz0 [a,e,] cycloheptatrienylidene) -piperidine STEPA.PREPARATION OF l-CYANOd-(zS-DIBENZO 11,13] -CYCLOHEPTATRIENYLIDENE)-PIPERIDINE A solution of1-methyl-4-(5-dibenzo[a,e]cycloheptatrienylidene)-piperidene (8.9 g.,0.031 mole) in 20 ml.

of dry benzene was added dropwise to a stirred solution of cyanogenbromide (3.6 g., 0.034 mole) in 15 ml. of benzene at room temperature.When approximately half of the solution had been added a white solidbegan to separate. When the addition was complete, 15 ml. of benzene wasadded to facilitate stirring and the mixture stirred for 75 minutes,then allowed to stand overnight.

After the addition of 50 ml. of absolute ether the product was'collectedand recrystallized from a mixture of acetone and absolute alcohol. Theyield of product, M.P., 203- 205 C. was 6.18-g. (67%).

An analytical sample, prepared by recrystallizing the roduct from asimilar experiment from acetone and subsequently from ethyl acetate,melted at 203.5-

Analysis.Calculated for C H N C, 84.53; H, 6.08;

N, 9.39. Found: C, 84.62; H, 6.30; N, 9.58.

STEP B.PREPARATION 0F '4-(5-DIBENZO[A,E]CYCLO- HEPTATRIENYLIDENE)PIPERIDINE HYDROCHLO- RIDE 1-cyano-4- S-dibenzo [a,e]cycloheptatrienylidene) -piperidine (6.18 g., 0.0206 mole) was heated torefluxing in a mixture of 150 ml. of glacial acetic acid, ml. of

water and 15 ml. of concentrated hydrochloric acid for 16 hours. Thesolution was concentrated until solid began to separate (volumeapproximately ml.) and diluted with 100 ml. of water. The Whitecrystalline product was collected and dried at 65 C. The yield ofproduct, M.P., 290292 C. (with decomposition) was 5.8 g. (91%).

Y Analysis.-Calculated for C HlgN'HCIZ C, 77.53; H,

6.51; N, 4.52.- Found: C, 77.46; H, 6.51; N, 4.54.

STEP C,--PREPARATION OF 4-(5-DIBENZO[A,E]CYCLO- HEPTATRIENYLIDENE)-PIPERIDINE The hydrochloride of4-(5-dibenzo[a,e]cycloheptatrienylidene)-piperidine was converted to thebase by suspending it in water addingbenzene and an excess of sodiumhydroxide and shaking the mixture till the solid dissolved. Evaporation.of the benzene left the crystalline base that was purified byrecrystallization from a mixture of alcohol and Water, followed byrecrystallization from a mixture of benzene and hexane.

Analysis.--Calculated for C I-I -N: C, 87.87; H, 7.01; N, 5.12. Found:C, 88.13; H, 7.05; N, 5.09.

EXAMPLE VIII 1 -eIhyl-4-(5-dibenz0 [cw] cycloheptatrienylidene)-piperidine hydrogen maleate 4 (5 dibenzo[a,e]cycloheptatrienylidene)piperidine (1.093 g., 0.004 mole) was dissolved in 25 ml. of dry t-butylalcohol. Potassium t-butoxide (4.5 m1. of a 0.97 molar solution int-butyl alcohol) was added followed by 0.624 g. (0.004 mole) of ethyliodide. The solution was allowed to stand at room temperature for 20hours then heated on the steam-bath for 2 hours. In order to removeunreacted starting material, ethyl chlorocarbonate (0.5 ml.) andpyridine (0.5 ml.) were added to the cooled solution which then wasstirred 30 minutes at room temperature, heated on the steam-bath for 15minutes, cooled and treated with 10 ml. of water followed by 10 ml. of1.25 N sodium hydroxide solution. Benzene was added and the benzeneextract separated and washed with Water. The basic material wasextracted into 200 ml. of 0.05 molar citric acid solution. The acidicextract then was made basic and the basic material extracted intobenzene. Evaporation of the benzene and drying the residue on thesteam-bath under reduced pressure gave 048 g. of a viscous yellow oilthat was dissolved in 95% ethanol and added to a solution of 0.203 g. ofmaleic acid in 95% ethanol. The solution was concentrated and dilutedwith ether. The white crystalline product, M.P., 202.5203.5 C. weighed0.57 g. Further recrystallization from mixtures of alcohol and ethergave material melting at 203.5204.5 C.

Ana!ysis.Calculated for C H N-C H O C, 74.80; H, 6.52; N, 3.36. Found:C, 74.59; H, 6.54; N, 3.44.

EXAMPLE IX 1 propyl 4 (5 dibenz[a,e]cycl0heptatrienylidene)- piperidinehydrogen maleate 4 dibenzo[a,e] cycloheptatrienylidene)-piperidine (5.47g., 0.02 mole) and sodamide (0.78 g., 0.02 mole) were heated torefluxing in 50 ml. of toluene for 15 hours. The light brown turbidsolution was cooled to room temperature and n-propyl iodide (3.40 g.,0.02 mole) was added. The mixture was stirred at room temperature for 1hour during which time a fiocculent light brown precipitate separated.The mixture then was heated on the steam-bath for 1 hour and finally atreflux for 30 minutes. After cooling to room temperature, 50 ml. ofwater was added to the reaction mixture which then was diluted with 200ml. of hexane. The aqueous layer was separated and the organic layerwashed with additional portions of water. After standing for days atroom temperature the solution had deposited some prismatic crystals thatwere separated by filtration. The solution then was concentrated to avolume of approximately 25 ml. In order to remove unreacted startingmaterial, maleic anhydride (4.70 g., 0.05 mole) in 35 ml. of benzene wasadded and the solution refluxed for 20 minutes. Methanol, 5 1111., thenwas added to destroy the excess maleic anhydride and the solution wasconcentrated to a volume of approximately 25 ml., and transferred to aseparator-y funnel. Hexane, 200 ml., water, 200 ml. and triethanolamine(14.9 g., 0.1 mole) were added and the mixture shaken. After theseparation was complete the clear yellow organic layer was separated andwashed with water. Evaporation of the solvent and drying the residue onthe steam-bath under reduced pressure gave 4.42 g. of a clear lightbrown residue. This material was dissolved in absolute alcohol andtreated with a solution of 1.79 g. (0.0154 mole) of maleic acid inabsolute alcohol. The hydrogen maleate of 1-propyl-4-(5-dibenzo[a,e]cycloheptatrienylidene) piperidine, M.P. 214-215 C. weighed5.42 g. Recrystallization from npropyl alcohol gave product M.P. 214216C. (sintered at 213 C.).

Analysis.Calculated for C H N'C H O 'C, 75.15; H, 6.77; N, 3.25. Found:C, 75.34; H, 6.86; N, 3.23.

EXAMPLE X 1 allyl 4 (5 dibenz0[a,e]cycl0hap-tatrienylidene)- piperidinehydrogen maleate The procedure of Example IX was followed, substituting2.42 g. (0.02 mole) of allyl bromide for the n-propyl iodide. Theproduct was isolated by substantially the same procedure. The productmelted at 175177 C. after recrystallization from a mixture of alcoholand ether followed by recrystallization from n-propyl alcohol.

Analysis.Calculated for C H N'C H O C, 75.50; H, 6.34; N, 3.26. Found:C, 75.21; H, 6.42; N, 3.28.

EXAMPPLE XI 1 (Z-hydroxyethyl) 4 (5 dibenz0[a,e]cycloheptatri enylidene)-piperidine 4 (5 dibenzo[a,e]cycloheptatrienylidene)-piperidine (5.47g., 0.02 mole) was dissolved in 109 ml. of ethanol. The solution wascooled to 0 C. and ethylene oxide was passed in until the gain in weightwas 1.76 g. The container then was stoppered and heated to 65-70 C. inan autoclave for 1 hour. The solvent then was distilled and the lasttraces of alcohol and water removed by azeotropic distillation withbenzene. The crystalline residue was extracted with boiling hexane andrecrystallized from a mixture of benzene and hexane. Furtherrecrystallization from mixtures of alcohol and water gave product, MP.158-159 C.

Analysis.Calculated for C H NO: C, 83.24; H, 7.30; N, 4.41. Found: C,83.00; H, 7.29; N, 4.38.

EXAMPLE XII 1 (2 methane snlfonyloxyethyl) 4 (5 dibenzo[a,e]-cycloheptatrienylidene)-piperidine hydrochloride 1 (2 hydroxyethyl) 4 (5dibenzo[a,e]cycloheptatrienylidene)-piperdine (2.10 g., 0.00662 mole)was dissolved in ml. of. dry acetonitrile. A solution ofmethanesulfo-nic anhydride (1.22 g., 0.007 mole) in 4 ml. ofacetonitrile was added and the solution allowed to stand at roomtemperature for 48 hours. Some crystals that had been deposited wereseparated by decantation and approximately 50 m1. of acetonitrile wasdistilled at 35-45 C. under reduced pressure. After 3 days in therefrigerator the solution was filtered to remove the solid that hadseparated and the solvent evaporated at 2535 C. under reduced pressure.The syrupy residue, the methanesulfonic acid salt of the product,weighed 3.32 g. It was dissolved in 13 ml. of absolute alcohol andtreated with 0.84 ml. of an 8.9 N solution of dry hydrogen chloride inabsolute alcohol. Absolute ether was added portionwise to precipitatethe hydrochloride. The product was recrystallized by dissolving it inabsolute methanol, warming the solution in a bath at 30 C. andcautiously adding ether to incipient turbidity. The product melted at130.5 134 C. with eifervescence.

Analysis.Calculated for C H O NS-HCl: C, 63.95; H, 6.07; Cl, 8.21; N,3.24; S, 7.42. Found: C, 64.47; H, 6.22; Cl, 8.02; N, 3.24; S, 7.35.

EXAMPLE H11 1 (,6 dimethylaminoethyl) 4 (5dibenz0[a,e]cycloheptatrienylidene)-piperidine dihydrogen dimaleate 4 (5dibenzo[a,e]cycloheptatrienylidene)-piperidine (5.47 g., 0.02 mole) andsodarnide (1.64 g., 0.042 mole) were heated to refluxing in 50 ml. oftoluene for 3 hours. ,B-Dimethylaminoethyl chloride hydrochloride (3.17g., 0.022 mole) was added to the warm solution. Stirring and refluxingthen were resumed and were continued for 12 hours. The reaction mixturethen was filtered and the solvent evaporated on the steam-bath underreduced pressure. The residue contained a white crystalline solid. Itwas taken up in ether and shaken with water till the solid dissolved.The ether layer then was separated, washed with water and evaporated.The residue, a clear dark brown resin, weighed 6.31 g. It was dissolvedin benzene, 25 m1. and treated with a solution of 4.70 g. (0.05 mole) ofmaleic anhydride in 50 ml. of benzene. The dark brown solution wasrefluxed on the steam-bath for 20 minutes. The Warm mixture then wastreated with ml. of absolute methanol. The dark brown solution wasdecanted from a black tarry solid that had separated. The solid wasshaken with a solution of 6 g. (0.15 mole) of sodium hydroxide in 100ml. of water. Nearly all the black solid dissolved. This solution wasadded to the benzene layer. A heavy emulsion resulted. Water, 100 ml.and benzene, 100 ml. were added without effecting a separation. Ether,100ml was added. A clear yellow organic phase separated and a tanprecipitate collected in the water layer. The organic layer wasseparated and the aqueous layer filtered. The precipitate dissolvedreadily in water. This solution was extracted with ether and the extractcombined with the organic layer. The combined organic layers then werewashed with water. Evaporation of the solvent and drying the residue onthe steam-bath under reduced pressure left 3.35 g. of residue. Theresidue was dissolved in absolute alcohol and treated with a solution of2.48 g. (0.021 mole) of maleic acid in absolute alcohol. The productseparated as a white crystalilne solid, M.P. 192193 C. (sintered at 190C.) in a yield of 4.29 g. Recrystallization from absolute alcohol raisedthe MP. to 193-1945" C.

Analysis-Calculated for C H N -2C H O C, 66.65; H, 6.29; N, 4.86. Found:C, 66.51; H,f6.26; N, 4.80.

EXAMPLE XIV 1-metIzyl-4-(3-methoxy-5-dibenzo[a,e]cyclolzepiatrienylidene) -piperidine hydrogen maleate Bysubstituting 3-methoxydibenzo[a,e]cycloheptatrien- 5-one for the3-chlorodibenzo[a,e]cycloheptatrien-S-one of Example VI and followingsubstantially the method of Example Vl,1-methyl-4-(S-methoxy-S-dibenzo[a,e]cycloheptatrienylidene)-piperidinehydrogen maleate is obtained.

The 3-methoxydibenzo[a,e]cycloheptatrien-S-one is obtained by thesequence employed for the preparation of 3-chlorodibenzo[a,e]cycloheptatrien-5-one except that 3 (pmethoxybenzylidene)-phthalide is reduced to2-(p-methoxyphenethyl)-benzoic acid by the three step method of W.Treibs and H. Klinkhammer [Chemische Berichte, 84,671 (1951)] instead ofemploying the hydriodic acid method. 1

EXAMPLE'XV 1-methyl-4-(3-flu0r0-5-a'ibenzo [a,e] cyclohepratrienylid ene-pi peridine hydrogen maleate 1 2 EXAMPLE XVI 1-methyl-4-(1-bromo-5-dibenz0 [a,e] cycloheptatrierzylidene) -piperidine hydrogenmaleate EXAMPLE XVII 1 -methyl (3,7-dichl0r0-5-dibenzo [a,e]cycloheptatrieny liderze) -piperidine By substituting3,7-dichlorodibenzo[a,e]-cycloheptatrien-S-one for the3-chlorodibenzo[a,e]cycloheptatrien-5- one of Example VI and followingsubstantially the method of Example VI,l-methyl(3,7-dichloro-5-dibenzo[a,e]- cycloheptatrienylidene)piperidineis obtained.

The 3,7 dichlorodibenzo{a,e]cycloheptatrien-S-one is prepared from3,7-dinitrodibenzo[a,e]cycloheptatrien-5- one by reducing the nitrogroups to amino and replacing the amino groups by chlorine, employingthe Sandmeyer reaction. The dinitrodibenzocycloheptatrienone is preparedby the method of T. W. Campbell, R. Ginsig and H. Schmid, Helv. Acta 36,1489 (1953).

EXAMPLE XVIII 1 -methyl-4- (4-methyl-10,1 1 -dzhydr0-5-dibenzo [me]-cycloheptatrienylidene) -piperidine hydrogen maleate By substituting4-methyl-10,11-dihydrodibenzo[a,e]- cyclOheptatrien-S-one for the10,11-dihydrodibenzo[a,e]- cycloheptatrien-S-oneof Example V andfollowing substantially the procedure of Example V, 1-methyl-4-(4-methyl 10,11 dihydro S dibenzo[a,e]cycloheptatrienylidene)-piperidine isobtained. The product is isolated as the hydrogen maleate salt.

The 4 methyl 10,11 dihydro 5 dibenzo[a,e]- cyclohept-atrien-5one isprepared by the cyclization of 2-methyl-6-phenethylbenzoic acid withpolyphosphoric acid under the conditions for the cyclization ofZ-phenethylbenzoic acid described by T. W. Campbell, R. Ginsig and H.Schmid, Helv. Chim. Acta 36, 1489 (1953).

EXAMPLE XIX 1 methyl 4 (10,11 dihydro 2,3 dimethyl 7 isopropyl 5dibenzo[a,e]cycloheptatrienylidene) piperidiize hydrochloride Bysubstituting10,11-dihydro-2,3-dimethyl-7-isopropyldibenzo[a,e]cycloheptatrien-S-onefor the 10,11-dihydrodibenzo[a,e] cycloheptatrien-S-one of Example V andfollowing substantially the procedure of Example V, 1- methyl 4 (10,11dihydro 2,3 dimethyl 7 isopropyl 5 dibenzo[a,e]cycloheptatrienylidene)-piperidine hydrochloride is obtained.

The 10,11 dihydro 2,3 dimethyl 7isopropyl-dibenzoIa,e]cycloheptatrien-S-one is prepared by the followingsequence. 4,5-dimethylphthalic anhydride is condensed withp-isopropylphenylacetic acid to give3-(p-isopropylbenzylidene)-phthalide. Reduction with phosphorus andhydriodic acid gives 2- (p-isopropylphenethyl)-4,5- dimethylbenzoicacid. The acid is cyclized to the desired ketone by the action ofpolyphosphoric acid as described by T. W. Campbell, R. Ginzig and H.Schmid, Helv. Chim. Acta 36, 1489 (1953).

13 EXAMPLE XX 1 methyl 4 (10,11 dihydro 2,3 dichloro 7- methyl 5dibenz[a,e]cyclohepmtrienylidene) piperidiize hydrochloride Bysubstituting10,11-dihydr0-2,3-dich1oro-7-methyl-dibenzo[a,e]cycloheptatrien-S-onefor the 10,11-dihydr0dibenzo[a,e]cycloheptatrien-S-one of Example V andfollowing substantially the procedure of Example V, 1- methyl 4 (10,11dihydro 2,3 dichloro 7 methyl- 5 dibenzo[a,e]cycloheptatrienylidene)piperidine hydrochloride is obtained.

The 10,11 dihydro 2,3 dichloro 7 methyldibenzo[a,e]cycloheptatrien-S-oneis prepared by the sequence of reactions employed for the preparation of10, 11 dihydro 2,3 dimethyl 7 isopropyldibenzo[a,e]-cycloheptatrien-S-one, described in Example XIX, employing4,5-dichlorophtha1ic anhydride and p-methylphenylacetic acid as startingmaterials.

This application is a contination-in-part of my copending US. patentapplication, Serial No. 763,809, now abandoned, filed September 29,1958.

What is claimed is:

1. A compound selected from the group consisting of:

ii if? m 1} X piperidine.

4. 1 methyl 4 (10,11-dihydro-5-dibenzo[a,e]cycloheptatrienylidene-piperidine.

5. 1 methyl 4 (3-chloro-5-dibenzo[a,e]c-ycloheptatrienylidene)-piperidine.

6. 4 (5 dibenzo[a,e]cycloheptatrienylidene)-piperidine.

7. 1 (2hydroxyethyl)-4-(5-dibenzo[a,e]cycloheptatrienylidene)-piperidine.

8. The compound 1 methyl-4-(5-dibenzo[a,e]-cycloheptatrienylidene)-piperidine.

9. The compound 1-me-thyl-4-(5-dibenzo[a,e]-cyclo-'heptatrienylidene)-piperidine hydrochloride hydrate.

References Cited in the file of this patent UNITED STATES PATENTS2,498,431 Lee Feb. 21, 1950 2,599,364 Berger et al. June 3, 19522,739,968 Sperber et al. Mar. 27, 1956 2,985,660 Judd et a1. May 23,1961 FOREIGN PATENTS 535,142 Canada Jan. 1, 1957 925,468 Germany Mar.21, 1955

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF: